Several types of effector cells, such as monocytes, neutrophils, and natural killer (NK) cells, have cell surface receptors that bind the Fc portion of immunoglobulins (Igs). When such cells encounter target cells that have been opsonized with immunoglobulin antibodies, they form conjugates, and either lyse or phagocytose the target cells, depending upon the effector cell type, the target cell type and the specific Fc receptor type (FcR) involved.
It has been demonstrated that target cell conjugation with an effector cell and lysis can also be induced by a covalently cross-linked bispecific heteroantibody made up of both anti-Fc receptor antibody and antibody directed against a target cell epitope. When effector cells bind such heteroaggregates to their Fc receptor, they can specifically bind and lyse target cells which have not been opsonized, but which express the appropriate target antigen (See e.g. U.S. patent application Ser. No: 972,871; Karpovsky et al. (1984) J Exp. Med. 160:1686-1701). Segal et al. have reported cytolysis of tumor cells by mouse monocytes with an attached heteroantibody which joins the Fc receptor of the monocyte on one end with tumor cell epitopes on the other end (See U.S. Pat. No. 4,676,980). Recently, a variety of bispecific monoclonal antibodies and immunotoxins have been shown to confer antitumor effects in vitro as well in vivo (See e.g., World Patent No: 9208892; Pan et al (1990) J Immunol., 145:267-275; Trail et al. (1993) Science (Washington, D.C.), 261:212-215; Weiner et al. (1993) J Immunol., 151:2877-2886; Link et al. (1993) Blood, 81:3343-3349; and Vallera, D. A. (1994) Blood, 83:309-317).
The binding of a heteroantibody to FcR is mediated by the Fc region of the antibody. This binding is ordinarily susceptible to inhibition by physiological concentrations of immunoglobulin. However, monoclonal antibodies, which bind to a site on the Fc receptor distinct from the binding site for endogenous immunoglobulin, have been produced (see, for example, Anderson et al., J Biol. Chem. 261:12856(1986); and Shen et al., J Immunol. 137:3378-3382 (1986)). These antibodies are useful as the effector-specific moiety of heteroantibodies, because serum immunoglobulin does not interfere with targeted effector cell killing.
Methods for making novel antibodies to the Fc receptor or in vivo methods for testing the efficacy of an antibody for administration in humans would be useful.